VE-818: An Investigational Live Biotherapeutic Product for Intestinal Diseases

I. Executive Summary

VE-818 is an investigational live biotherapeutic product (LBP) originated and currently under development by Vedanta Biosciences, Inc..[1] This product is classified within the "Bacteria" therapeutic class and is designed to function through mechanisms described as "Bacteria replacements" and "Gastrointestinal microbiome modulators".[1]

The development of VE-818 has advanced to Phase 2 clinical trials, with a primary focus on addressing intestinal diseases.[1] Notably, current Phase 2 investigations are specifically evaluating the potential of VE-818 to reduce enteropathogen colonization and ameliorate environmental enteropathy in pregnant women, a significant area of unmet medical need in certain global regions.[1]

Findings from Phase 1 clinical studies, conducted in healthy adult volunteers, indicated that VE-818 was well tolerated. These initial studies provided crucial insights into its clinical pharmacology, demonstrating that robust colonization of the gut by the VE-818 bacterial strains could be achieved, particularly when preceded by vancomycin pretreatment. The persistence of this colonization was also found to be influenced by the duration of VE-818 administration. A key pharmacodynamic observation from these early trials was an association between VE-818 administration and an increase in stool concentrations of secondary bile acids, metabolites known for their immunoregulatory functions.[3]

The strategic progression of VE-818 into Phase 2 trials specifically targeting pregnant women underscores the potential perceived favorable safety profile emerging from Phase 1 evaluations.[1] Phase 1 trials are fundamentally designed to assess the safety and tolerability of an investigational product in healthy individuals.[3] Advancing to a vulnerable population such as pregnant women, who require stringent safety standards for any intervention, suggests that the initial safety data for VE-818 were encouraging. Environmental enteropathy and associated enteropathogen colonization represent substantial health burdens during pregnancy in certain geographical areas, impacting both maternal and infant health outcomes. Targeting this complex condition indicates Vedanta Biosciences' aim to address a specific and significant unmet clinical need.

A critical operational detail emerging from Phase 1 is the requirement of vancomycin pretreatment to ensure robust colonization by the VE-818 strains.[3] Vancomycin is an antibiotic known to significantly alter the gut microbiota by reducing the populations of certain bacteria. This necessity for pretreatment suggests that the native gut microbiome may otherwise present a barrier to the effective engraftment and persistence of the VE-818 consortium, a phenomenon known as colonization resistance. This implies that creating a more receptive intestinal niche through antibiotic-mediated "clearing" is an important component of the VE-818 therapeutic strategy. This factor has considerable implications for the design of the overall treatment regimen, including considerations of potential antibiotic-associated effects and the subsequent ecological dynamics within the gut microbiome following such perturbation and LBP administration.

II. Introduction to VE-818

VE-818 is an investigational live biotherapeutic product (LBP) being developed by Vedanta Biosciences, Inc..[1] Vedanta Biosciences specializes in the research and development of rationally defined bacterial consortia intended for therapeutic use, aiming to modulate the host's microbiome and elicit specific physiological responses.

The development of VE-818 is situated within Vedanta Biosciences' broader platform focused on microbiome-derived therapeutics. The company's systematic approach to LBP development was highlighted by presentations at Digestive Disease Week (DDW) 2022, which included analyses of VE818 alongside other candidates like VE202 (for inflammatory bowel disease) and VE303 (for Clostridioides difficile infection).[3] These presentations underscore a strategy based on common learnings in clinical pharmacology, such as understanding colonization dynamics and the impact of pretreatment regimens across their portfolio of defined bacterial consortia.[3] This suggests a methodical, platform-driven drug development process rather than the pursuit of isolated candidates.

The primary therapeutic area designated for VE-818 is "Intestinal Diseases" [1], also categorized under the broader term "Digestive System Disorders".[1] This focus is inherently aligned with the nature of LBPs, which are designed to exert their effects directly within the gastrointestinal tract and its associated microbial ecosystem.

Consistent with its nature as an LBP, VE-818 is not classified as a New Molecular Entity (NME).[2] LBPs typically comprise well-characterized, often naturally occurring, bacterial strains. While the individual strains may not be novel chemical entities, their specific combination, formulation, and therapeutic application represent the innovation. This classification has distinct regulatory implications, potentially influencing pathways for approval and market exclusivity compared to traditional NMEs.

III. Drug Classification and Proposed Mechanism of Action

VE-818 is categorized as a "Live biotherapeutic product" (LBP), a class of therapeutics defined by the presence of live microorganisms, such as bacteria, intended for the prevention, treatment, or cure of a disease or condition.[1] Within this classification, it is further specified as belonging to the "Bacteria" class, denoting its composition from bacterial strains.[2]

The proposed mechanisms of action (MoA) for VE-818 are described as "Bacteria replacements" and "Gastrointestinal microbiome modulators".[1]

• Bacteria Replacements: This aspect of the MoA suggests that VE-818, as a defined consortium of live bacteria [3], is designed to colonize the host's gastrointestinal tract. Upon successful engraftment, these strains may directly compete with or inhibit the growth of pathogenic or otherwise undesirable microorganisms. Such competitive exclusion could occur through various means, including competition for essential nutrients, occupation of mucosal adhesion sites, or the localized production of antimicrobial substances.
• Gastrointestinal Microbiome Modulators: This indicates a broader capacity of VE-818 to influence the existing microbial ecosystem beyond simple replacement. Administration of VE-818 may lead to alterations in the composition, diversity, metabolic activity, or functional output of the resident gut microbiota, thereby guiding the ecosystem towards a state considered healthier or more resilient.

A significant pharmacodynamic effect observed in Phase 1 studies, which elaborates on its role as a microbiome modulator, is the association of VE818 colonization with increased stool concentrations of secondary bile acids.[3] This increase was noted as early as the first week of treatment. Secondary bile acids, such as deoxycholic acid and lithocholic acid, are products of microbial metabolism of primary bile acids in the colon. These metabolites are recognized for their diverse physiological activities, including potent immunomodulatory functions, influence on gut barrier integrity, and direct or indirect antimicrobial effects against certain pathogens. The modulation of secondary bile acid profiles by VE-818 thus represents a plausible indirect mechanism through which the LBP could exert therapeutic benefits by influencing host biochemistry and immune responses.

The dual MoA involving "Bacteria replacements" and "Gastrointestinal microbiome modulators" [1] points towards a comprehensive therapeutic strategy. The observed increase in secondary bile acids [3] offers a tangible example of microbiome modulation that could causally link VE-818 administration to beneficial host outcomes. For instance, specific secondary bile acids are known to interact with host receptors like the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5), which play roles in regulating inflammation, metabolism, and gut barrier function. These effects are highly pertinent to the pathophysiology of inflammatory intestinal conditions and environmental enteropathy.

The evolution of VE-818's developmental focus from an "undisclosed indication" during its Phase 1 study [3] to the specific and complex indication of "environmental enteropathy in pregnant women" for Phase 2 trials [1] may have been guided by these early mechanistic insights. Environmental enteropathy is characterized by chronic gut inflammation, impaired nutrient absorption, and heightened susceptibility to pathogens. The potential of VE-818 to modulate host immunity and gut barrier function, possibly via alterations in secondary bile acid profiles, provides a strong scientific rationale for its investigation in this challenging condition.

Table 1: Overview of VE-818

Feature	Description	Source(s)
Originator	Vedanta Biosciences, Inc.	1
Drug Type	Live biotherapeutic product	1
Class	Bacteria	2
Mechanism of Action	Bacteria replacements, Gastrointestinal microbiome modulators; Associated with increased secondary bile acid production	1
Therapeutic Area	Intestinal Diseases, Digestive System Disorders	1
Highest Current Development Phase	Phase 2	1

IV. Clinical Development Program

The clinical development of VE-818 has progressed from initial Phase 1 studies in healthy volunteers to planned Phase 2 trials targeting specific intestinal disease indications.[1]

A. Phase 1 Clinical Studies

Phase 1 clinical evaluation of VE-818 was conducted in healthy adult volunteers in the United States.[2] These studies employed a double-blind, placebo-controlled design to rigorously assess the safety and initial pharmacodynamic effects of the LBP.[3] One such study involved 74 subjects who received VE-818 orally (PO).[2] The dosing regimens explored were comprehensive, including low and high doses of VE-818 or placebo, administered for durations of either one or 14 days. A critical aspect of the study design was the incorporation of cohorts that received vancomycin antibiotic pretreatment versus those who did not, allowing for an assessment of the impact of prior gut microbiota perturbation on VE-818 engraftment.[3]

The primary objectives of these Phase 1 trials were to establish the safety and tolerability profile of VE-818.[3] Secondary objectives focused on characterizing the colonization dynamics of the constituent bacterial strains within the human gastrointestinal tract.[3]

Key findings from the Phase 1 program for VE-818 were:

• Safety and Tolerability: VE-818 was reported to be well tolerated by the healthy adult participants.[2] Establishing a favorable safety profile is a fundamental step for any LBP candidate.
• Colonization Dynamics:
• A significant finding was the necessity of vancomycin pretreatment to achieve "robust strain colonization".[3] This suggests that altering the existing gut microbial community structure is crucial for the effective engraftment and persistence of the VE-818 strains.
• The colonization by VE-818 strains was observed to be "persistent in most subjects through the end-of-study visit," which occurred six months after the cessation of treatment.[3] This indicates the potential for VE-818 to induce durable changes in the gut microbiome.
• The duration of VE-818 administration (one day versus 14 days) was identified as "an important driver of long-term persistence of colonization".[3] This finding provides valuable information for optimizing dosing schedules in subsequent therapeutic trials to achieve sustained microbial modulation.
• Pharmacodynamic Effects: A notable pharmacodynamic observation was that colonization with VE-818 was "associated with increased stool concentrations of secondary bile acids... as early as the first week of treatment".[3] The report highlighted that secondary bile acids possess "several beneficial immunoregulatory functions." This suggests that VE-818 may exert therapeutic effects not only through direct microbial interactions but also by modulating host physiology via the metabolic byproducts of its constituent strains.

B. Phase 2 Clinical Studies

Following the Phase 1 program, VE-818 has advanced into Phase 2 clinical development.[1] The current focus of the Phase 2 trials is to evaluate the "Ability of the Probiotic VE818 to Reduce Enteropathogen Colonization and Improve Environmental Enteropathy in Pregnant Women".[1] This specific and complex indication addresses a significant public health issue in certain global regions. The selection of this indication for Phase 2, particularly after an "undisclosed indication" in Phase 1 [3], suggests that the Phase 1 pharmacodynamic findings, such as the modulation of secondary bile acids known for their roles in gut barrier function and immune regulation, provided a strong mechanistic rationale. Environmental enteropathy, characterized by gut inflammation, malabsorption, and increased pathogen susceptibility, is a condition where such microbiome-modulating effects could be therapeutically relevant.

The Phase 2 trials are planned for conduct in Bangladesh, Pakistan, Zambia, and Burkina Faso, countries where environmental enteropathy is prevalent and significantly impacts maternal and child health.[1]

Three specific Phase 2 Investigator-Initiated Trials (IITs) have been identified:

• NCT06817031: A Phase 2 IIT which, according to the available information, is "Not yet recruiting".[1]
• PACTR202404835984424: A Phase 2 IIT reported with a status of "Suspended".[1]
• PACTR202404797704972: Another Phase 2 IIT, also reported with a status of "Suspended".[1]

The general design for these Phase 2 studies is described as randomized, placebo-controlled, and intended as proof-of-concept investigations.[1] The "Suspended" status of two PACTR-registered trials is a noteworthy development. While the reasons for suspension are not detailed in the provided information, such occurrences in clinical development can stem from various factors, including logistical complexities, funding considerations, interim data reviews (safety or futility), or broader strategic shifts. The "Not yet recruiting" status of the NCT-registered trial suggests that this arm of the Phase 2 program may be at an earlier stage of operationalization or facing distinct preparatory timelines.

The requirement for vancomycin pretreatment, identified as crucial for robust colonization in Phase 1 [3], is a significant clinical pharmacology insight that would likely inform the design and execution of these Phase 2 trials. The administration of an antibiotic pretreatment, especially in a vulnerable population like pregnant women, would necessitate careful consideration of the risk-benefit profile, including potential impacts on the maternal and developing fetal microbiome beyond the intended facilitation of VE-818 engraftment. Standardization of this "conditioning" step would be essential for ensuring comparability and interpretability of the Phase 2 trial results.

Table 2: Summary of VE-818 Clinical Trials

Trial ID / Reference	Phase	Status	Indication/Population	Key Objectives/Endpoints	Key Design Features	No. of Subjects	Location(s)	Source(s)
Phase 1 (DDW 2022 Report)	Phase 1	Completed	Healthy Volunteers	Safety, Tolerability, Colonization Dynamics, Secondary Bile Acid Production	Double-blind, placebo-controlled, oral admin, low/high dose, 1 or 14 days, +/- vancomycin pretreatment	74	USA	2
NCT06817031	Phase 2	Not yet recruiting	Environmental Enteropathy in Pregnant Women	Reduce enteropathogen colonization, Improve environmental enteropathy	Randomized, placebo-controlled, proof-of-concept	N/A	Bangladesh, Pakistan, Zambia, Burkina Faso	1
PACTR202404835984424	Phase 2	Suspended	Environmental Enteropathy in Pregnant Women	Reduce enteropathogen colonization, Improve environmental enteropathy	Randomized, placebo-controlled, proof-of-concept	N/A	Bangladesh, Pakistan, Zambia, Burkina Faso	1
PACTR202404797704972	Phase 2	Suspended	Environmental Enteropathy in Pregnant Women	Reduce enteropathogen colonization, Improve environmental enteropathy	Randomized, placebo-controlled, proof-of-concept	N/A	Bangladesh, Pakistan, Zambia, Burkina Faso	1

N/A: Not available in the provided snippets.

V. Regulatory Status

Based on the available information, the regulatory status of VE-818 includes the following points:

• Orphan Drug Status: VE-818 has not been assigned Orphan Drug Status.[2]

Orphan Drug Designation is a regulatory status granted to medicines intended for the diagnosis, prevention, or treatment of life-threatening or chronically debilitating rare diseases. The criteria for "rare" typically involve a prevalence below a certain threshold in a given population (e.g., fewer than 200,000 people in the United States, or not more than 5 in 10,000 in the European Union). The absence of this designation for VE-818 could suggest several possibilities: the target indications, such as environmental enteropathy, while potentially severe and with high unmet need in specific geographic regions 1, may not meet the formal definition of a rare disease in major regulatory jurisdictions where such designations confer significant development incentives. Alternatively, Vedanta Biosciences may not have pursued this designation at the current stage of development, or the condition's prevalence, even if concentrated, might exceed typical orphan criteria when considered within the populous regions targeted for Phase 2 trials.

• New Molecular Entity (NME) Status: VE-818 is explicitly listed as "No" for New Molecular Entity status.[2]

This classification is consistent with VE-818's nature as a live biotherapeutic product. LBPs are generally composed of existing, often well-characterized, bacterial strains. The novelty and inventiveness typically lie in the specific selection and combination of these strains into a defined consortium, their formulation, and their intended therapeutic application, rather than the discovery of a new chemical structure. This distinction from NMEs (which are typically novel small molecules or large biologic proteins) influences the regulatory review process, manufacturing considerations (e.g., ensuring consistency of a multi-strain product), and the scope and nature of market exclusivity that may be granted upon approval.

The regulatory journey for LBPs is evolving, with agencies like the U.S. Food and Drug Administration (FDA) providing specific guidance for their development. The classification of VE-818 as a non-NME LBP will shape its path through these regulatory frameworks.

VI. Conclusion

VE-818, an investigational live biotherapeutic product developed by Vedanta Biosciences, Inc., represents a targeted approach to modulating the human gut microbiome for therapeutic benefit. Currently in Phase 2 of clinical development, VE-818 is a defined consortium of bacterial strains.

The proposed mechanism of action for VE-818 centers on its ability to act as a "Bacteria replacement" and a "Gastrointestinal microbiome modulator".[1] Early clinical data from Phase 1 studies have provided initial support for this, demonstrating that VE-818 can successfully colonize the human gut, particularly following vancomycin pretreatment, and that this colonization is associated with an increase in stool concentrations of secondary bile acids.[3] These microbial metabolites are known for their immunoregulatory properties, suggesting a potential pathway through which VE-818 may exert beneficial effects on host physiology. The Phase 1 studies also established a satisfactory safety and tolerability profile in healthy adult volunteers and yielded important insights into colonization dynamics, such as the impact of dosing duration on the persistence of the bacterial strains.[3]

The clinical development strategy for VE-818 appears to be hypothesis-driven, transitioning from an undisclosed indication in Phase 1 to a specific and challenging indication—the reduction of enteropathogen colonization and improvement of environmental enteropathy in pregnant women—for its Phase 2 program.[1] This focus addresses a significant unmet medical need in specific global regions and aligns with the potential immunomodulatory and gut barrier-enhancing effects suggested by the preclinical rationale and Phase 1 findings. This targeted approach is characteristic of the advanced development of next-generation microbiome therapeutics, moving beyond less characterized probiotic formulations to well-defined consortia with plausible biological mechanisms.

However, the progression of the Phase 2 program faces some uncertainty, as two of the three identified trials are currently listed as "Suspended".[1] While the reasons for these suspensions are not detailed in the available information, this status highlights the inherent complexities and potential setbacks in clinical drug development.

In summary, VE-818 holds promise as a rationally designed microbiome therapeutic. Its future clinical utility is contingent upon the successful execution and positive outcomes of its Phase 2 and subsequent Phase 3 trials, particularly in demonstrating robust efficacy and continued safety in the targeted patient populations. The requirement for antibiotic pretreatment and the long-term persistence and functional impact of the consortium will remain key areas of investigation and consideration for its ultimate application.

Works cited

1. VE-818 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed June 13, 2025, https://synapse.patsnap.com/drug/04339681f2cd449190598fa3728320c7
2. VE 818 - AdisInsight - Springer, accessed June 13, 2025, https://adisinsight.springer.com/drugs/800068688
3. Vedanta Presents Data from Multiple Studies at Digestive Disease Week 2022 Annual Meeting, accessed June 13, 2025, https://www.vedantabio.com/press-release/vedanta-presents-data-from-multiple-studies-at-digestive-disease-week-2022-annual-meeting/